The study of collagen production (fibrosis) in systemic sclerosis (SSc) has been ongoing since the 70's and yet there are no FDA approved antifibrotic drugs for SSc, although recently one drug was assigned as a break- through therapy. Thus, SSc still represents a critical unmet medical need. The upregulation of collagen expres- sion by various cytokines has been extensively studied and yet the export of procollagen from the endoplasmic reticulum (ER) remains unstudied in SSc or any human fibrotic disease. The long-term goal of our laboratory is to develop therapeutically useful antifibrotics for SSc. The overall objectives in this application are to (1) to elucidate the molecular mechanisms that upregulate procollagen export proteins in the ER in SSc fibroblasts and (2) define the role for caspase-1 and XBP1s in this upregulation. The central hy- pothesis is that the augmented nuclear localization of the transcription factor XBP1s in SSc myofibro- blasts enhances the expression of procollagen export proteins. This coordinated series of events needs caspase-1 and XBP1s, enabling the greater export of type I procollagen from the ER leading to fibrosis. The rationale for this project is that a determination of the mechanism(s) that lead to the upregulation of procollagen export proteins would offer a strong scientific framework whereby the development of clinically relevant antifibrotics is realized. This central hypothesis will be tested in two specific aims: 1) to identify which procollagen export proteins are upregulated during SSc fibrosis and define the role for IL-1 or TGF-?1 in their upregulation and 2) to identify how caspase-1 and XBP1s upregulates procollagen export during fibrosis. In the first aim, we will study how COPII proteins and procollagen export proteins are upregulated in fibroblast cell lines derived from patients with SSc. These experiments will identify the role for IL-1 and TGF-?1 in this process. For the second aim, we will use NLRP3-KO and XBP1-KO fibroblasts and define how caspase- 1 upregulates procollagen export during fibrosis. We expect IRE1? to be central in this process. The research proposed in this application is innovative. It will focus our understanding toward human fibrosis and the func- tional role for IL-1 and TGF-?1 in the export of procollagen from the ER. An added innovation is the study of caspase-1 in this process. Our findings will contribute significantly to our understanding of procollagen I export in a human fibrotic disease. Currently the gap in our understanding of how procollagen I is released from the ER in human fibrotic disorders is large. The expected results from our studies shall identify checkpoints in this export pathway and allow for the design of specific therapeutics that will target and control fibrosis. We expect these results to have an important positive impact for the development of a new class of antifibrotics.